Inhibition of nitric oxide interrupts the accumulation of CD8+ T cells surrounding Plasmodium berghei-infected hepatocytes

Abstract

The elimination of liver-stage malaria parasites by nitric oxide (NO)-producing hepatocytes is regulated by T cells. Both CD8 ؉ and CD4 ؉ T cells, which surround infected hepatocytes, are evident by 24 h after sporozoite challenge in Brown Norway rats previously immunized with irradiated Plasmodium berghei sporozoites. While the number of CD4 ؉ T cells remained the same beyond 24 h postchallenge, the number of CD8 ؉ T cells increased three-and sixfold by 31 and 44 h, respectively. This increase in the number of CD8 ؉ T cells correlated with a decrease in the number of intrahepatic parasites. In immunized rats, intrahepatic parasites were reduced in number by 31 h after sporozoite challenge and cleared from the liver by 44 h, as visualized by P. berghei-specific DNA in situ hybridization. If immunized rats were treated with aminoguanidine, a substrate inhibitor of NO synthase, at the time of challenge, liver-stage protection was blocked, as shown by the increase in parasite liver burden. Further histological examination of infected livers from immunized animals treated with aminoguanidine revealed fewer and smaller cellular infiltrates surrounding the infected hepatocytes, and the number of CD8 ؉ T cells that normally accumulate within the infiltrates was drastically reduced. Consequently, the infected hepatocytes were not cleared from the liver. We hypothesize that the early production of NO may promote the influx and/or enhance local proliferation of malaria parasite-specific CD8 ؉ T cells or a CD8 ؉ T-cell subset which is required for parasite clearance.

The Response of Mice to Infection by the Parasitic Nematode Trichinella: A Comparison of Trichinella Spiralis and Trichinella Pseudospiralis

“…Cells marked with CDS in uninfected control mice remain at 3% of lymphocytes. These results are supported by Scheller, et al (1997) who found that, in animals infected with the intracellular parasite Plasmodium berghei, CD8+ (and CD4+) cells increased up to six-fold and that CTL are essential for parasite clearance from infected animals. These same researchers have suggested that, at least for animals infected with Plasmodium, NO production is regulated by both CD4+ and CD8+ T lymphocytes.…”

The role of intrahepatic lymphocytes in mediating protective immunity induced by attenuated Plasmodium berghei sporozoites

“…In frozen liver sections from attenuated spz-immune rodents, fluorescent labeling revealed the presence of CD8 + and CD4 + T cells and macrophages. The infiltrates showed a significant (6-fold) increase in the number of CD8 + T cells after spz challenge, with no increase in the number of CD4 + T cells (33).…”

Expression of inducible nitric oxide synthase (iNOS) mRNA in target organs of lethal and non‐lethal strains of murine malaria

“…There are reports that iNOS activity during murine malaria either remains unchanged (32) or is implicated in the liver rather than the spleen, for example, high levels of hepatic iNOS mRNA in immunized mice challenged with P. yoelii sporozoites (33) or P. berghei (27). Liver from immunized BALB/c mice expresses maximal amounts of iNOS mRNA 12-24 h after challenge with irradiated P. berghei ANKA sporozoites (34). This observation, together with an earlier report that induction of NOS by stimulated hepatocytes prevented the development of parasites in hepatocytes, suggests that iNOS may be important in the liver of immune mice (27).…”